tbuckley/cabot-search huggingface dataset:
Autophagy in health and disease: From molecular mechanisms to therapeutic target
Authors: Guang Lu, Yu Wang, Yin Shi, Zhe Zhang, Canhua Huang, Weifeng He, Chuang Wang, Han‐Ming Shen
Journal: MedComm (2022)

Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.
Polyglycerol and Poly(ethylene glycol) exhibit different effects on pharmacokinetics and antibody generation when grafted to nanoparticle surfaces
Authors: Kwangsoo Shin, Hee-Won Suh, Julian Grundler, Anna Y. Lynn, Jinal U. Pothupitiya, Zoe M. Moscato, Melanie Reschke, Laura G. Bracaglia, Alexandra S. Piotrowski-Daspit, W. Mark Saltzman
Journal: Biomaterials (2022)
Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity
Authors: Xiaoxiao Ma, Nadeem Riaz, Robert M. Samstein, Mark Lee, Vladimir Makarov, Cristina Valero, Diego Chowell, Fengshen Kuo, Douglas Hoen, Conall W. R. Fitzgerald, Hui Jiang, Jonathan Alektiar, Tyler J. Alban, Ivan Juric, Prerana Bangalore Parthasarathy, Yu Zhao, Erich Y. Sabio, Richa Verma, Raghvendra M. Srivastava, Lynda Vuong, Wei Yang, Xiao Zhang, Jingming Wang, Lawrence K. Chu, Stephen L. Wang, Daniel W. Kelly, Xin Pei, Jiapeng Chen, Rona Yaeger, Dmitriy Zamarin, Ahmet Zehir, Mithat Gönen, Luc G. T. Morris, Timothy A. Chan
Journal: Nature Genetics (2022)
Exposome Profiles and Asthma among French Adults
Authors: Alicia Guillien, Annabelle Bédard, Orianne Dumas, Julien Allegre, Nathalie Arnault, Audrey Bochaton, Nathalie Druesne-Pecollo, Dorothée Dumay, Léopold K. Fezeu, Serge Hercberg, Nicole Le Moual, Hugo Pilkington, Stéphane Rican, Guillaume Sit, Fabien Szabo de Edelenyi, Mathilde Touvier, Pilar Galan, Thierry Feuillet, Raphaëlle Varraso, Valérie Siroux
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Although previous studies in environmental epidemiology focused on single or a few exposures, a holistic approach combining multiple preventable risk factors is needed to tackle the etiology of multifactorial diseases such as asthma. Objectives: To investigate the association between combined socioeconomic, external environment, early-life environment, and lifestyle-anthropometric factors and asthma phenotypes. Methods: A total of 20,833 adults from the French NutriNet-Santé cohort were included (mean age, 56.2 yr; SD, 13.2; 72% women). The validated asthma symptom score (continuous) and asthma control (never asthma, controlled asthma, and uncontrolled asthma) were considered. The exposome (n = 87 factors) covered four domains: socioeconomic, external environment, early-life environment, and lifestyle-anthropometric. Cluster-based analyses were performed within each exposome domain, and the identified profiles were studied in association to asthma outcomes in negative binomial (asthma symptom score) or multinomial logistic (asthma control) regression models. Measurements and Main Results: In total, 5,546 (27%) individuals had an asthma symptom score ⩾1, and 1,206 (6%) and 194 (1%) had controlled and uncontrolled asthma, respectively. Three early-life exposure profiles ("high passive smoking-own dogs," "poor birth parameters-daycare attendance-city center," or "⩾2 siblings-breastfed" compared with "farm-pet owner-molds-low passive smoking") and one lifestyle-anthropometric profile ("unhealthy diet-high smoking-overweight" compared with "healthy diet-nonsmoker-thin") were associated with more asthma symptoms and uncontrolled asthma. Conclusions: This large-scale exposome-based study revealed early-life and lifestyle exposure profiles that were at risk for asthma in adults. Our findings support the importance of multiinterventional programs for the primary and secondary prevention of asthma, including control of specific early-life risk factors and promotion of a healthy lifestyle in adulthood.
NAD+ salvage governs mitochondrial metabolism, invigorating natural killer cell antitumor immunity
Authors: Xiaowei Guo, Siyu Tan, Tixiao Wang, Renhui Sun, Shuangjie Li, Panpan Tian, Mengzhen Li, Yuzhen Wang, Yankun Zhang, Yuchuan Yan, Zhaoru Dong, Lunjie Yan, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Kazuya Yamagata, Lifen Gao, Chunhong Ma, Tao Li, Xiaohong Liang
Journal: Hepatology (2022)

Natural killer (NK) cells are key players in tumor immunosurveillance, and metabolic adaptation manipulates their fate and functional state. The nicotinamide adenine dinucleotide (NAD + ) has emerged as a vital factor to link cellular metabolism and signaling transduction. Here, we identified NAD + metabolism as a central hub to determine the homeostasis and function of NK cells.NAD + level was elevated in activated NK cells. NAD + supplementation not only enhanced cytokine production and cytotoxicity but also improved the proliferation and viability of NK cells. Intriguingly, the salvage pathway was involved in maintaining NAD + homeostasis in activated NK cells. Genetic ablation or pharmacological blockade of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD + salvage pathway, markedly destroyed the viability and function of NK cells. Mechanistically, NAD + salvage dictated the mitochondrial homeostasis and oxidative phosphorylation activity to support the optimal function of NK cells. However, in human HCC tissues, NAMPT expression and NAD + level were significantly down-regulated in tumor-infiltrating NK cells, which negatively correlated with patient survival. And lactate accumulation in the tumor microenvironment was at least partially responsible for the transcriptional repression of NAMPT in NK cells. Further, deficiency of Nampt in NK cells accelerated the growth of HCC and melanoma. Supplementation of the NAD + precursor nicotinamide mononucleotide (NMN) significantly improved NK antitumor response in both mouse and human cell-derived xenografts.These findings reveal NAD + salvage as an essential factor for NK-cell homeostasis and function, suggesting a potential strategy for invigorating NK cell-based immunotherapy.
Machine learning-based quantitative prediction of drug exposure in drug-drug interactions using drug label information
Authors: Ha Young Jang, Jihyeon Song, Jae Hyun Kim, Howard Lee, In-Wha Kim, Bongki Moon, Jung Mi Oh
Journal: npj Digital Medicine (2022)

Many machine learning techniques provide a simple prediction for drug-drug interactions (DDIs). However, a systematically constructed database with pharmacokinetic (PK) DDI information does not exist, nor is there a machine learning model that numerically predicts PK fold change (FC) with it. Therefore, we propose a PK DDI prediction (PK-DDIP) model for quantitative DDI prediction with high accuracy, while constructing a highly reliable PK-DDI database. Reliable information of 3,627 PK DDIs was constructed from 3,587 drugs using 38,711 Food and Drug Administration (FDA) drug labels. This PK-DDIP model predicted the FC of the area under the time-concentration curve (AUC) within ± 0.5959. The prediction proportions within 0.8-1.25-fold, 0.67-1.5-fold, and 0.5-2-fold of the AUC were 75.77, 86.68, and 94.76%, respectively. Two external validations confirmed good prediction performance for newly updated FDA labels and FC from patients'. This model enables potential DDI evaluation before clinical trials, which will save time and cost.
Food-seeking behavior is triggered by skin ultraviolet exposure in males
Authors: Shivang Parikh, Roma Parikh, Keren Michael, Lior Bikovski, Georgina Barnabas, Mariya Mardamshina, Rina Hemi, Paulee Manich, Nir Goldstein, Hagar Malcov-Brog, Tom Ben-Dov, Ohad Glaich, Daphna Liber, Yael Bornstein, Koral Goltseker, Roy Ben-Bezalel, Mor Pavlovsky, Tamar Golan, Liron Spitzer, Hagit Matz, Pinchas Gonen, Ruth Percik, Lior Leibou, Tomer Perluk, Gil Ast, Jacob Frand, Ronen Brenner, Tamar Ziv, Mehdi Khaled, Shamgar Ben-Eliyahu, Segev Barak, Orit Karnieli-Miller, Eran Levin, Yftach Gepner, Ram Weiss, Paul Pfluger, Aron Weller, Carmit Levy
Journal: Nature Metabolism (2022)

Abstract Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown. Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year. In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males. In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin. Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53–chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.
Tumour necrosis factor inhibitor use during pregnancy is associated with increased birth weight of rheumatoid arthritis patients’ offspring
Authors: Hieronymus T W Smeele, Esther Röder, Annemarie G M G J Mulders, Eric A P Steegers, Radboud J E M Dolhain
Journal: Annals of the Rheumatic Diseases (2022)

To study pregnancy outcomes in a closely monitored, well-defined cohort of women with rheumatoid arthritis (RA). In particular, pregnancy outcomes of women that used a TNFi during pregnancy.
Expanded Dataset Reveals the Emergence and Evolution of DNA Gyrase in Archaea
Authors: Paul Villain, Ryan Catchpole, Patrick Forterre, Jacques Oberto, Violette da Cunha, Tamara Basta
Journal: Molecular Biology and Evolution (2022)

Abstract DNA gyrase is a type II topoisomerase with the unique capacity to introduce negative supercoiling in DNA. In bacteria, DNA gyrase has an essential role in the homeostatic regulation of supercoiling. While ubiquitous in bacteria, DNA gyrase was previously reported to have a patchy distribution in Archaea but its emergent function and evolutionary history in this domain of life remains elusive. In this study, we used phylogenomic approaches and an up-to date sequence dataset to establish global and archaea-specific phylogenies of DNA gyrases. The most parsimonious evolutionary scenario infers that DNA gyrase was introduced into the lineage leading to Euryarchaeal group II via a single horizontal gene transfer from a bacterial donor which we identified as an ancestor of Gracilicutes and/or Terrabacteria. The archaea-focused trees indicate that DNA gyrase spread from Euryarchaeal group II to some DPANN and Asgard lineages via rare horizontal gene transfers. The analysis of successful recent transfers suggests a requirement for syntropic or symbiotic/parasitic relationship between donor and recipient organisms. We further show that the ubiquitous archaeal Topoisomerase VI may have co-evolved with DNA gyrase to allow the division of labor in the management of topological constraints. Collectively, our study reveals the evolutionary history of DNA gyrase in Archaea and provides testable hypotheses to understand the prerequisites for successful establishment of DNA gyrase in a naive archaeon and the associated adaptations in the management of topological constraints.
Heart Failure With Reduced Ejection Fraction: “The Importance of Being Frail”
Authors: Linda R. Peterson, Andrew R. Coggan
Journal: Circulation (2022)

scar Wilde, in his famous play, recognized the Importance of Being Earnest.Cardiologists recognize the importance of exercise training (ET) in the rehabilitation of heart failure with reduced ejection fraction (HFrEF).Pandey et al have now put the spotlight on 'the importance of ' frailty in the response to ET. Frailty is characterized by diminished physiological function, reduced physiologic reserve, and increased vulnerability to acute stressors. 1,2It appears to affect >1 of every 2 patients. 1,3This frequency is roughly double that of community-dwelling adults more than 90 years of age. 4 This high burden of frailty in HFrEF has a tremendous monetary and human cost.It is associated with poorer exercise tolerance, poorer quality of life, and a 50% higher risk of hospitalization and death. 5Paradoxically, frailty is also associated with a lower likelihood of being on goaldirected medical therapy 1 or enrollment in cardiac rehabilitation. 6It is clear that frailty has a profound effect on patients with HFrEF and exposes an area where more study is needed to test therapies and improve outcomes.
Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity
Authors: Yasir Y. Elamin, Jacqulyne P. Robichaux, Brett W. Carter, Mehmet Altan, Hai Tran, Don L. Gibbons, Simon Heeke, Frank V. Fossella, Vincent K. Lam, Xiuning Le, Marcelo V. Negrao, Monique B. Nilsson, Anisha Patel, R.S.K. Vijayan, Jason B. Cross, Jianjun Zhang, Lauren A. Byers, Charles Lu, Tina Cascone, Lei Feng, Rajyalakshmi Luthra, Francis A. San Lucas, Geeta Mantha, Mark Routbort, George Blumenschein, Anne S. Tsao, John V. Heymach
Journal: Cancer Cell (2022)

We report a phase II study of 50 advanced non-small cell lung cancer (NSCLC) patients with point mutations or insertions in EGFR exon 20 treated with poziotinib (NCT03066206). The study achieved its primary endpoint, with confirmed objective response rates (ORRs) of 32% and 31% by investigator and blinded independent review, respectively, with a median progression-free survival of 5.5 months. Using preclinical studies, in silico modeling, and molecular dynamics simulations, we found that poziotinib sensitivity was highly dependent on the insertion location, with near-loop insertions (amino acids A767 to P772) being more sensitive than far-loop insertions, an observation confirmed clinically with ORRs of 46% and 0% observed in near versus far-loop, respectively (p = 0.0015). Putative mechanisms of acquired resistance included EGFR T790M, MET amplifications, and epithelial-to-mesenchymal transition (EMT). Our data demonstrate that poziotinib is active in EGFR exon 20-mutant NSCLC, although this activity is influenced by insertion location.
Obesity enriches for tumor protective microbial metabolites and treatment refractory cells to confer therapy resistance in PDAC
Authors: Kousik Kesh, Roberto Mendez, Beatriz Mateo-Victoriano, Vanessa T Garrido, Brittany Durden, Vineet K Gupta, Alfredo Oliveras Reyes, Nipun Merchant, Jashodeep Datta, Santanu Banerjee, Sulagna Banerjee
Journal: Gut Microbes (2022)

Obesity causes chronic inflammation and changes in gut microbiome. However, how this contributes to poor survival and therapy resistance in patients with pancreatic cancer remain undetermined. Our current study shows that high fat diet-fed obese pancreatic tumor bearing mice do not respond to standard of care therapy with gemcitabine and paclitaxel when compared to corresponding control diet-fed mice. C57BL6 mice were put on control and high fat diet for 1 month following with pancreatic tumors were implanted in both groups. Microbiome of lean (control) and obese (high fat diet fed) mice was analyzed. Fecal matter transplant from control mice to obese mice sensitized tumors to chemotherapy and demonstrated extensive cell death. Analysis of gut microbiome showed an enrichment of queuosine (Q) producing bacteria in obese mice and an enrichment of S-adenosyl methionine (SAM) producing bacteria in control diet-fed mice. Further, supplementation of obese animals with SAM sensitized pancreatic tumors to chemotherapy. Treatment of pancreatic cancer cells with Q increased PRDX1 involved in oxidative stress protection. In parallel, tumors in obese mice showed increase in CD133+ treatment refractory tumor populations compared to control animals. These observations indicated that microbial metabolite Q accumulation in high fat diet-fed mice protected tumors from chemotherapy induced oxidative stress by upregulating PRDX1. This protection could be reversed by treatment with SAM. We conclude that relative concentration of SAM and queuosine in fecal samples of pancreatic cancer patients can be developed as a potential biomarker and therapeutic target in chemotherapy refractory pancreatic cancer.
Colocalization of Gene Expression and DNA Methylation with Genetic Risk Variants Supports Functional Roles of <i>MUC5B</i> and <i>DSP</i> in Idiopathic Pulmonary Fibrosis
Authors: Raphael Borie, Jonathan Cardwell, Iain R. Konigsberg, Camille M. Moore, Weiming Zhang, Sarah K. Sasse, Fabienne Gally, Evgenia Dobrinskikh, Avram Walts, Julie Powers, Janna Brancato, Mauricio Rojas, Paul J. Wolters, Kevin K. Brown, Timothy S. Blackwell, Tomoko Nakanishi, J. Brent Richards, Anthony N. Gerber, Tasha E. Fingerlin, Norman Sachs, Sara L. Pulit, Zachary Zappala, David A. Schwartz, Ivana V. Yang
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Common genetic variants have been associated with idiopathic pulmonary fibrosis (IPF). Objectives: To determine functional relevance of the 10 IPF-associated common genetic variants we previously identified. Methods: We performed expression quantitative trait loci (eQTL) and methylation quantitative trait loci (mQTL) mapping, followed by co-localization of eQTL and mQTL with genetic association signals and functional validation by luciferase reporter assays. Illumina multi-ethnic genotyping arrays, mRNA sequencing, and Illumina 850k methylation arrays were performed on lung tissue of participants with IPF (234 RNA and 345 DNA samples) and non-diseased controls (188 RNA and 202 DNA samples). Measurements and Main Results: Focusing on genetic variants within 10 IPF-associated genetic loci, we identified 27 eQTLs in controls and 24 eQTLs in cases (false-discovery-rate-adjusted P < 0.05). Among these signals, we identified associations of lead variants rs35705950 with expression of MUC5B and rs2076295 with expression of DSP in both cases and controls. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. We also demonstrated strong co-localization of eQTL/mQTL and genetic signal in MUC5B (rs35705950) and DSP (rs2076295). Functional validation of the mQTL in MUC5B using luciferase reporter assays demonstrates that the CpG resides within a putative internal repressor element. Conclusions: We have established a relationship of the common IPF genetic risk variants rs35705950 and rs2076295 with respective changes in MUC5B and DSP expression and methylation. These results provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.
Multitier mechanics control stromal adaptations in the swelling lymph node
Authors: Frank P. Assen, Jun Abe, Miroslav Hons, Robert Hauschild, Shayan Shamipour, Walter A. Kaufmann, Tommaso Costanzo, Gabriel Krens, Markus Brown, Burkhard Ludewig, Simon Hippenmeyer, Carl-Philipp Heisenberg, Wolfgang Weninger, Edouard Hannezo, Sanjiv A. Luther, Jens V. Stein, Michael Sixt
Journal: Nature Immunology (2022)

Abstract Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.
Response by Lam and Gerstein to Letter Regarding Article, “Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial”
Authors: Carolyn S.P. Lam, Hertzel C. Gerstein
Journal: Circulation (2022)
Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1
Authors: Nathaniel W. Mabe, Min Huang, Guillermo N. Dalton, Gabriela Alexe, Daniel A. Schaefer, Anna C. Geraghty, Amanda L. Robichaud, Amy S. Conway, Delan Khalid, Marius M. Mader, Julia A. Belk, Kenneth N. Ross, Michal Sheffer, Miles H. Linde, Nghi Ly, Winnie Yao, Maria Caterina Rotiroti, Benjamin A. H. Smith, Marius Wernig, Carolyn R. Bertozzi, Michelle Monje, Constantine S. Mitsiades, Ravindra Majeti, Ansuman T. Satpathy, Kimberly Stegmaier, Robbie G. Majzner
Journal: Nature Cancer (2022)
<i>N</i> <b>6</b> -Methyladenosine and Its Implications in Viruses
Authors: Yafen Wang, Xiang Zhou
Journal: Genomics Proteomics & Bioinformatics (2022)

Abstract N 6-methyladenine (m6A) is the most abundant RNA modification in mammalian messenger RNAs (mRNAs), which participates in and regulates many important biological activities, such as tissue development and stem cell differentiation. Due to an improved understanding of m6A, researchers have discovered that the biological function of m6A can be linked to many stages of mRNA metabolism and that m6A can regulate a variety of complex biological processes. In addition to its location on mammalian mRNAs, m6A has been identified on viral transcripts. m6A also plays important roles in the life cycle of many viruses and in viral replication in host cells. In this review, we briefly introduce the detection methods of m6A, the m6A-related proteins, and the functions of m6A. We also summarize the effects of m6A-related proteins on viral replication and infection. We hope that this review provides researchers with some insights for elucidating the complex mechanisms of the epitranscriptome related to viruses, and provides information for further study of the mechanisms of other modified nucleobases acting on processes such as viral replication. We also anticipate that this review can stimulate collaborative research from different fields, such as chemistry, biology, and medicine, and promote the development of antiviral drugs and vaccines.